Oxidative stress plays a critical role in skin aging and in various dermatological disorders by promoting inflammation, apoptosis, and cellular dysfunction. Among reactive oxygen species (ROS), hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) readily penetrates cell membranes, triggering oxidative damage. This study investigated the protective effects of the <i>Dendranthema boreale</i> (Makino) Ling ex Kitam. flower extract (DBE) against H<sub>2</sub>O<sub>2</sub>-induced oxidative stress in HaCaT keratinocytes and explored the underlying molecular mechanisms. DBE (30-80 μg/ml) significantly attenuated H<sub>2</sub>O<sub>2</sub>-induced cytotoxicity by reducing cleaved caspase-3 activation and lowering the Bax/Bcl-2 ratio, thereby inhibiting apoptosis. Furthermore, DBE selectively suppressed JNK and ERK phosphorylation while having no effect on p38 MAPK activation. Inflammatory responses were also modulated, as DBE inhibited NF-κB p65 phosphorylation and downregulated COX-2 expression, a key mediator of oxidative stress-induced inflammation. These findings indicate that DBE protects HaCaT keratinocytes from oxidative stress-induced cellular damage by promoting cell survival, suppressing apoptosis, and modulating the key signaling pathways involved in oxidative stress and inflammation. This study provides foundational insights into the potential therapeutic and cosmetic applications of DBE for the prevention of oxidative stress-related skin disorders.